Coronary heart disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principle cause of death in the United States. Although historically much emphasis has been placed on total plasma cholesterol levels as a risk factor for coronary heart disease, it has been clearly established that low levels of high density lipoprotein cholesterol (HDL-C) is an independent risk factor for this disease. Family and twin studies have shown that there are genetic components that affect HDL levels. However, mutations in the main protein components of HDL (ApoAl and ApoAII) and in the enzymes that are known to be involved in HDL metabolism (e.g., CETP, HL, LPL and LCAT) do not explain all of the genetic factors affecting HDL levels in the general population (J. L. Breslow, in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; and S. M. Grundy, (1995) J Am. Med. Assoc. 256: 2849). This finding in combination with the fact that the mechanisms of HDL metabolism are poorly understood, suggests that there are other as yet unknown factors that contribute to the genetic variability of HDL levels.
Another disorder that is often associated with high triglyceride and low high density lipoprotein (HDL) concentrations is obesity, which renders a subject susceptible to cardiovascular diseases, such as ischemia, restenosis, congestive heart failure, and atherosclerosis. Severely obese individuals (weighing 60% over a normal weight) have a high risk of developing cardiorespiratory problems. They are also at risk of developing chronic hypoventilation, which can lead to hypercapnia, pulmonary hypertension, and heart failure. Severe episodic hypoxia, which can cause arrhythmias and sudden death, is 10 times more common in the severely obese. Severely obese individuals are also at increased risk of suffering from obstructive sleep apnea, pickwickian syndrome (i.e., daytime hypoventilation, somnolence, polycythemia, cor pulmonale), and renal vein thrombosis. ("Cecil Essentials of Medicine", Andreoli et al., Third Edition, 1993, W. B. Saunders Company).
Moderate obesity (corresponding to a weight between 20-60% above normal weight) poses increased risk of early mortality. Obese individuals suffer more frequently than non obese individuals from hypertension. Type II diabetes mellitus can also be aggravated by excess weight. Obesity can also increase the risk of a subject developing cholelithiasis and endometrial carcinoma.
One candidate factor that is likely to be involved both in obesity and cardiovascular disease is the SR-BI receptor, which has been shown to bind HDL and LDL cholesterol and mediate uptake into cells (Acton, S. et al., (1996) Science 271:518-520). SR-BI is likely to contribute to genetic lipoprotein variability, thereby playing a role in the development of lipid metabolism disorders and thus generally, cardiovascular diseases.
In addition, cholesterol gallstone formation could be caused by a defective SR-BI receptor, since the SR-BI receptor is likely to be involved in transferring HDL-cholesterol from extrahepatic tissues to the liver (reverse cholesterol transport) e.g. for incorporation into bile (J. L. Breslow, in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; S. M. Grundy, (1995) J. Am. Med. Assoc. 256: 2849; G. Assman, A. von Eckardstein, H. B. Brewer Jr. in The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2053-2072; W. J. Johnson et al., (1991) Biochem. Biophys. Acta 1085:273; M. N. Pieters et al., (1994) Ibid 1225:125; and C. J. Fielding and P. E. Fielding, (1995) J. Lipid Res 36:211).
Further, a defective SR-BI receptor or abnormal levels of SR-BI receptor could influence the fertility of a subject, since SR-BI appears to be involved in HDL-cholesteryl ester delivery to steroidogenic tissues (ovary, adrenal glands and testis) for hormone synthesis (Acton, S. et al., (1996) Science 271:518-520; Landschulz, et al., (1996) J. Clin. Invest. 98:984-95; J. M. Anderson and J. M. Dietschy (1981) J. Biol. Chem. 256: 7362; M. S. Brown et al., (1979) Recent Prog Horm. Res. 35:215; J. T. Gwynne and J. F. Strauss III, (1982) Endocr. Rev. 3:299; B. D. Murphy et al., (1985) Endocrinology 116: 1587).
The SR-BI receptor (Scavenger Receptor-BI) is a scavenger receptor that mediates endocytosis of unmodified and modified lipoproteins, e.g., LDL, acetylated LDL, oxidized LDL (Acton et al. (1994) J. Biol. Chem. 269:21003), HDL ((Acton, S. et al., (1996) Science 271:518-520), anionic phospholipids (Rigotti et al. (1995) J. Biol. Chem. 270:16221), negatively charged liposomes and apoptotic cells (Fukasawa et al. (1996) Exp. Cell Res. 222:246). The human SR-BI receptor (also termed "CLA-1) exists in two differentially spliced forms (Calvo and Vega (1993) J. Biol. Chem. 268:18929). The predominant form of human SR-BI is a protein of 509 amino acids. The shorter form of the SR-BI receptor has 409 amino acids, and is lacking the 100 amino acids located 42 amino acids downstream of the initiation codon (Calvo and Vega, supra). The nucleotide sequence of a cDNA encoding human SR-BI is disclosed in Calvo and Vega, supra and the nucleotide sequence of a cDNA encoding hamster SR-BI is disclosed in Acton et al. (1994) J. Biol. Chem. 269:21003 and in PCT Application WO 96/00288.